SA01210740A - Extended release oral dosage composition. - Google Patents

Abstract

This invention demonstrates a two-layer compact steel composition comprising (a) a primary layer that is released immediately including an effective anti-allergic amount of dyslore atadine and at least one pharmaceutically acceptable excipient, (b) a second layer with a long-lasting release comprising an effective amount of Nasal decongestant and release agent that remains a pharmacy long acceptable and in which the composition contains less than about 2 per cent of the products for analysis of deslutadine.

Description

iN M Extended-Release Oral Dosage Composition Full Description BACKGROUND: This invention relates to a bilayer extended-release oral dosage formulation containing a nasal decongestant such as pseudoephedrine in a sealed-release core and a thin outer coating containing the non-sedating antihistamine desloratadine The © solid oral dosage formulations in this invention are useful in the treatment of patients suffering from symptoms and signs associated with allergic conditions and/or infections such as the common cold, as well as signs and symptoms associated with allergic conditions and/or inflammation of the skin or upper and lower airways such as allergic rhinitis and rhinitis. Seasonal allergic rhinitis, nasal congestion and respiratory illnesses. Allergic rhinitis 0 and nasal congestion. desloratadine was prescribed; It is also called discarbitoxyloratadine in US Patent No. 199,719; As a non-sedating antihistamine useful as an anti-allergic agent. US Patent No. 05549049918 describes methods and formulations for the treatment of Veo symptoms of seasonal allergic rhinitis with desloratadine. US Patent Nos. 5,440,570 and 5,001,176 describe a twice-daily extended-release film tablet in which the tablet coating contains descarbitoxyloratadine, a hydrophilic polymer and polyethylene glycol, and the tablet core contains acetamitophen, pseudoephedrine or its salt, and a biodegradable polymer. For ingestion, Yo Yo has pharmaceutically acceptable excipients. US Patent #5,915,699 describes an extended-release tablet that has a skeletal core containing sulfate and pseudoephedrine and a coating containing loratadine. what a

The uncoated twice-a-day oral dosage formulation was not described in the foregoing art. The successful development of a desloratadine-pseudoephedrine twice-a-day formulation is required but requires 1) obtaining a modified pattern of the pseudoephedrine component © for an extended period; by twelve hours while maintaining the safety and efficacy of desloratadine and?) reducing the formation of impurities due to the interaction between desloratadine and excipients in the pseudoephedrine class that are incompatible with desloratadine. The release is essentially stable and free of 0 impurities. Desloratadine is an additional polymorph that is effective and safe when used primarily twice a day or once a day for the treatment, healing and/or elimination of SLEW and symptoms associated with the common cold as well as allergic conditions and/or infections that affecting the skin or the upper and lower airways such as seasonal allergic rhinitis and nasal congestion General Description of the invention Yo We have discovered that desloranadine loses its color It decomposes in the presence of the excipients described in the previous field, and we discovered that these problems were solved mainly a) when the use of an acidic excipient was avoided in the desloratadine layer and when desloratadine was mixed with a pharmaceutically acceptable carrier medium containing a protective amount of desloratadine from a pharmaceutically acceptable base salt or b ) When a protective amount of desloratadine is present from a pharmaceutically acceptable 0-antioxidant in at least one layer and preferably at least one of these antioxidants is present in each layer in the layered AE tablet. oll The present invention describes a solid, two-layered, compressed formulation consisting of: 1) a first direct release layer containing an effective antiallergic amount of desloratadine and a protective amount of desloratadine from a calcium, magnesium, or aluminium-Yo salt insoluble in water base at least one pharmaceutically acceptable antioxidant or a protective amount of desloratadine (Y) release layer

“0 Z: a second extender containing an effective amount of pseudoephedrine or its salt and a pharmaceutically acceptable extended-release agent and optionally a protective amount of a pharmaceutically acceptable antioxidant desloratadine. Thus, in an embodiment,” the present invention describes a bilayer compressed solid composition consisting of ) 1 layer - a first direct release layer - contains an effective anti-allergenic amount of desloratadine and a protective amount of desloratadine of a pharmaceutically acceptable water insoluble calcium, magnesium or aluminum base and *) another layer - a second extended release layer - contains An effective amount of pseudoephedrine or its salt and a pharmaceutically acceptable extended-release agent.

AD And the pharmaceutical compositions in this invention contain less than about? In 1) 1-Formyldesloratadine (see chart N) of desloratadine degradation products as 1% RH for periods of 1 when these formulations are stored at 7*C and about 1 month. VA extended For example, about time and in a preferred embodiment; this invention describes a bilayer compressed solid VO composition consisting of: a) a first direct release layer containing sel | aes | and 0 b) a second extended release layer containing: : 0

0 Pseudoephedrine Sulfate YY. Hydroxypropyl Methyl Cellulose 018 Microcrystalline Cellulose A Povidone YA, Silicon Dioxide Oy Magnesium Stearate MM: Total in the second layer The mentioned two-layer compressed composition contains previously on less than about y percent of the degradation products of desloratadine IN Jie formyl-desloratadine (see Scheme 1) when these formulations are stored at 705*C and about 10 percent relative humidity for extended periods of Time of about VA month.(Jl 0) In another preferred embodiment; this invention also describes a bilayer compressed solid formulation consisting of 1) first direct release layer containing an antiallergic Lad amount of desloratadine and a protective amount Desloratadine has at least one pharmaceutically acceptable antioxidant and) a second extended-release layer containing an effective amount of psoraephraphedrine or its salt and a pharmaceutically acceptable extended-release agent and a buffering amount of 0. of about AY per cent of the desyl degradation product loratadine as 11-formyldesloratadine (see chart 1) when these formulations are stored at 7©5*C and about 10% RH for extended periods of time for about 18 months. The present invention describes a solid, bilayer compressed formulation consisting of a) a first direct-release layer containing an effective antiallergic amount of desloratadine® at least one pharmaceutically acceptable excipient and b) a second extended-release layer containing an effective amount of a nasal decongestant and Pharmacologically and incorporation acceptable extended release agent

i. In Vs preferably, the bilayer compressed solid formulation contains less than 100% of desloratadine degradation products as A1-formyl desloratadine after storage for 0.1 month and where at least about 860 percent of desloratadine dissolves in VA min. to m in about standard HCL and in another preferred embodiment. This invention also describes a solid, compressed formulation 0 first direct release layer containing 1) mg of bilayer containing desloratadine And a protective amount of desloratadine from calcium, magnesium or aluminum salt A second extended-release layer containing pharmaceutically acceptable water-insoluble base (Y) and pseudoephedrine sulfate mg pseudoephedrine sulfate and a pharmaceutically acceptable extended-release agent 181 per hour of VY and this preferred combination gives a 7 hour dose of desloratadine and a 0 dose of pseudoephedrine sulfate.

Ji, infections of the lower and upper airways, and skin involving a patient in need of such treatment is an effective amount of solid, compressed, two-layered formulation in this invention. Vo | Detailed Description: During the development period of the formulations of this invention; It was found that desfuratadine is not persistent and that its color fades when stored in combination with various excipients such as those described in the patent as part of the structural central part containing 0 04 NAY American Patent No. pseudoephedrine sulfate and includes the excipients that cause discoloration and Stability of 0 Je acids in water 1 less than PH Desloratadine Organic acidic excipients such as stearic acid, povidone, carpovidone, and carbon-containing substances on carbonyls such as lactose, ethyl cellulose, hydroxypropyl methyl cellulose, and binders Such as povidone and polymers such as hydroxypropyl methylcellulose are useful as polymeric frameworks for the extended release of pseudoephedrine sulfate from the central part of the inner polymeric YO structure.

We have also discovered that catalyst metal ions are involved in the formation of desloratadine degradation products. We have explored two solutions to inhibit and/or prevent the formation of desloratadine degradation products. In one of the preferred embodiments; A protective amount of a pharmaceutically acceptable antioxidant should be present for desloratadine in at least one of the two layers, preferably one of these antioxidants in each layer. and in a second favorite embodiment; We also discovered that it is possible to prepare a bilayer tablet containing desloratadine in a first direct-release layer in close contact with a second extended-release layer containing a nasal decongestant and excipients incompatible with desloratadine by using a buffer of desloratadine from a calcium salt or a magnesium VO or an acceptable water-insoluble basic aluminum (Lana) in the direct-release desloratadine layer. The term “sealed connection” as used herein when referring to the two layers that make up a layered SW disk refers to the absence of a thin interface between the two layers. The term “pharmaceutically acceptable antioxidant” as used herein when 1 in reference to desloratadine (formula 1 in the diagram) means a pharmaceutically acceptable chelating agent that protects desloratadine from the formation of degradation products including but not limited to those of formulas [1 to 7] mentioned In the scheme such as TN formyl desloratadine or 17-formil. . DL (Formula IT in the diagram), 11-hydroxylamine from DL (Formula V in the diagram), 17-oxide from DL (Formula TV in the diagram), 7-hydroxyl 17 -oxide .00 of DL (formula TIT in the chart) and the compositions mentioned in the chart were determined using standard physicochemical methods LC-MC (Fie and LC-NMR) and the appropriate anti-oxidants are the actual pharmaceutically acceptable for DL is Jal sal | Pharmacologically acceptable chelating agents such as those described in “CLS Agents” pp. 64 — 114 vol. © MC Kerth — Ortham in ENCYCLOPEDIA “OF CHEMICAL TECHNOLOGY Yo 4th ed. 1497 John Wiley &Sons; New York Preferably including but not limiting hydroquinic acids

L-carboxylic acid, io-tartaric acid, citric acid, gluconic acid and their pharmaceutically acceptable salts, aminocarboxylic acids, Jie, edetic acid (ethylenediaminetetraacetic acid) and its pharmaceutically acceptable salts, Jie, disodium EDTA, disodium EDTA, trisodium EDTA, and tetrasodium Sl and be second

© Disodium EDTA and citric acid are the preferred pharmaceutically acceptable antioxidants and hydroxycarboxylic acid and ascorbic acid are avoided. The protective amount of desloratadine from a pharmaceutically acceptable antioxidant in DL direct release layer 0 is in the range from about 1.1% to about 10% by weight and preferably about 1% to 8% or 1 percent to about 7 percent > 0 percent preferably from about ; per cent to about +” per cent or about; To about +% or more preferably from about ©% to about >% The protective amount of desloratadine from a pharmaceutically acceptable antioxidant in the PES extended release layer ranges in the range from about 0% to about 10% and preferably From about 1 percent to about 10 percent or about 1.1 percent to about ? In LIL Vo preferably more than about 1 to about ? Percent and most preferably about 1%. In a preferred embodiment of this invention, about 1% by weight of a pharmaceutically acceptable antioxidant such as disodium edetate is present in the PES extended-release layer. In another embodiment, about 6% by weight is present. From a mixture of two pharmaceutically acceptable antioxidants such as disodium edetate and citric acid in a direct DL release layer at a ratio of about 1:0# to about 1:© preferably about ©:1 and about 1 in the matrix that is oxidized Joma pharmaceutically as SE sodium EDTA present in the extended-release layer and in another embodiment there is about © in a ball by weight of a pharmaceutically acceptable antioxidant one e.g. disodium EDTA in the 3) direct DL layer. In another preferred embodiment; Approximately ¾ mg (YE hr source) of SDL yo direct release DL layer and 11 mg (11 hr source) of pseudoephedrine sulfate nasal decongestant are present in the direct release layer (see examples; and © and ). 1) and in one

Preferred Emulsions The dibasic phosphate salt and the dibasic calcium phosphate hydrate are preferred to be present in the direct DL release layer, and no pharmaceutically acceptable antioxidant is present in either layer (see JE); (source YE h) of DL and about 1.1 to about 10% of © at least one antioxidant in the direct release layer of DL and preferably about ; percent to about 1 percent of a mixture of two antioxidants weighted disodium edetate and citric acid in a ratio of #: 1 to 1:1 preferably in a ratio of #: 1 and about 11 percent to about 01 in percent and preferably about 1.1 percent to about © in math and preferably about 1 percent to about * percent and most preferably about 1 in ASL of Ys antioxidant Jie disodium edetate In extended-release PES class (see LEY 0 and 1). Desloratarine was found to have an acceptable direct release pattern of class II Av (percent release in) + 1101 N in less than approx. £0 min) and contains less than about ? Percent of the decomposition products of desloratadine after storage saad at least VA Vo month at "C and about 10 percent relative humidity (RH) and by "allergies and inflammations affecting the skin and airways" we mean those Cases and symptoms associated with allergies and inflammation affecting the skin and upper lower airways from the nose to the lungs, including allergic cases and actual infections affecting the skin, upper and lower airways, rhinitis, seasonal and perennial allergies, non-allergic rhinitis, and asthma, including allergic and non-allergic asthma, and sinusitis cold (in combination with an NSAID such as aspirin, ibuprofen, or acetaminophen) and/or decongestant jie pseudoephrine), dermatitis, especially allergic and exacerbated parotiditis, urticaria, and associated skin tattoos: with symptoms, in addition to retinopathy and small vessel disease associated with Yo' disease. diabetes.

Lo

The amount of desloratadine that is effective in treating or preventing an allergic reaction varies

Inflammation of the skin and the upper and lower airways of different ages and gender

Body weight and unit case of allergy and inflammation in the patient ‎(lady) range from the actual quantity

Desloratadine is effective in treating or preventing the occurrence of these allergic and inflammatory conditions in:

0 Range from about 7.5 mg/day to about 10 mg/day, preferably from about #,"mg/

day to about 17 mg/day or so; mg/day to about 11 mg/day or so

© mg/day to about 10 mg/day, preferably from about 0 mg/day to around 10

mg/day and most preferably about ∼5 mg/day—on a single dose or in two divided doses of 7.5 mg/day.

0 Desloratadine is a non-sedating extended-release antihistamine with potent HY receptor antagonist activity in the JE form and after oral administration; Loratadine rapidly hydrolyzes to desloratadine or desloratadine, which is a pharmacologicly active metabolite. An in vitro and in vivo animal pharmacological study was conducted to evaluate the different pharmacokinetic effects of desloratadine and loratadine.

Vo of antihistamine activity in idl (compared to p-value of 21050) Desloratadine was relatively free from causing changes in behavior or neurological or autonomic functions. The ability of desloratadine or loratadine to occupy 11 receptors in the brain of guinea pigs after administration into the peritoneum was evaluated. The results suggest Impaired central histamine receptor entry for desloranadine or loratadine.

7 In addition to the anti-histamine effect. Desloratadine showed anti-allergic and anti-inflammatory activity in several in vitro and in vivo tests. These in vitro tests (performed mainly on human cells) showed that desloratadine can inhibit several events in the allergic inflammatory cascade. The anti-inflammatory effects of desloratadine depend on the antagonistic effect of the receptor. H'

Yo of desloratadine include:

-11- histamine, tryptase, leukotrienes, and prostaglandins Jie release of inflammatory stimuli from somatic cells. Yo 11-13 and release of inflammatory cytokines to include 11-4, 11-6, and 11-8 (the post-activation regulator expressed winner RANTES Jie and release of inflammatory chemokines (presumably from normal cells); anionic superoxide production of neutrophils with polymorphic nuclei” and the expression of cell adhesion molecules such as intercellular adhesion molecules and ICAM- 1) B - selectin in the cells of the endocardium; F, migration and adhesion of eosinophilic cells. 0 It can be expected that a Lad-dependent effect can be expected. In vivo studies of desloratadine suggest constriction of allergic bronchial tubes and cough. The clinical efficacy and safety of desloratadine have been recorded in more than A patient with seasonal allergic rhinitis in ; Randomized clinical trials 0, double-blind, and the results of these studies showed the effectiveness of desloratadine in the treatment of patients Vo adults and adolescents with allergic rhinitis (related to allergies). Useful decongestants in this invention include phenylpropanolamine, phenylephrine, pseudoephedrine, and be Pseudoephedrine plus acid addition salts or 11:50 is a sympathomimetic drug that has been recognized by those experienced in this field as a safe and effective therapeutic agent in the treatment of 0

Oia) in the nose and is commonly taken orally and together with an antihistamine to treat the nose associated with allergic rhinitis. It is more preferable to use pseudoephedrine as a nasal decongestant in this invention, and it is preferable to use pseudoephedrine sulfate. During the period of developing the dosage formulation oral in this invention; It was discovered that Yo: the selection of polymers for the polymeric structural central part is effective for obtaining a period

17- 11 to 11 hours, preferably from 11, the required release extension, which is at least not given (Jal pseudoephedrine sulfate, for example, 11 hours, preferably at least as polymers CPS 1500850 or CPS 54060 Use of Hydroxypropyl Methylcellulose in the Skeletal Central Component This period of release is most preferred to be over an hour for a dose of pseudoephedrine sulfate and we have found that only by at least 11% of the selection for use in the structural core For specific weight ratios of three specific OV polymers, the desired pseudoephedrine release pattern was obtained only by mixing 0.15 part by weight of methyl hydroxypropyl methylprednisolone (about 1 part by weight preferably centipoise) with (7) about 1 part by weight 000001 (UPS 7718) cellulose 10 with (about) lism preferably 1 part by weight of thin crystalline cellulose 0 to 018 parts by weight poufhdone (per 117 parts by weight preferably 1718 to part by weight of hydroxypropyl methyl cellulose) on binder heath for at least 0 hours VY preferably for a period of SY) secondary This was the extended release pattern of Kabri Pseudoephedrine comes from the extended-release layer. The extended-release layer also contains certain amounts of silicon dioxide as a lubricant and magnesium stearate as a highly Vo material at level (SCU) strength cup unit £4Y sliding and the tablet hardness was not affected The high level of lubricant water (7 mg/tablet), but it is preferable to maintain the level of the material part of the weight of the lubricant to a part of the weight of 1/9 of the lubricant with povidone as a secondary binder. 'Lubricant' as used herein to a substance added to a dose to allow 0 to release the dosage form like a tablet after being compressed from the mold or vice versa. Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and the like, preferably stearates magnesium or. Talc is used here to a material such as anti-agent LS" and the term "Yo" refers to kneading sliding materials that improve the flow properties of the powdered mixture.

Q1 Suitable lubricants include silicon dioxide and talc, and it is preferable to use silicon dioxide. The term “substances” as used herein means any substance that may be added to pharmaceutical formulations to help keep such formulations together and release medicine from them. The appropriate binders are selected from those found in NF (National Formulas) No. (VA p. 77016 (1490) and include povidones, deformants, celluloses, alginates, gums and low weight hydroxypropyl methylcellulose. Particularly hydroxypropyl methylcellulose (YAY). The term “Water Irresistible Calcium, Magnesium, and Aluminum Salts Osi 0” as used herein means pharmaceutically acceptable calcium, magnesium, and aluminum carbonates, phosphates, silicates, or mixtures thereof. Such as calcium sulfate dihydrate, anhydrous magnesium sulfate, magnesium sulfate hydrate, dibasic calcium phosphate, dibasic calcium silicate, Vo basic, magnesium trihydrate, magnesium phosphate, aluminum silicate, magnesium phosphate hydrate, aluminum phosphate, calcium phosphate, and it is more preferable to use dibasic calcium phosphate hydrate. M A water insoluble base calcium, magnesium or aluminum salt is pharmaceutically acceptable in the range of about 00 to 1 in 0 percent of the DL direct release layer and the weight percentages of the base calcium, magnesium or aluminum salt are not Pharmaceutically acceptable water soluble in the range from about 1 A to about 56: 1, preferably in the range from about 1:01 to about: 1:01: the most sais in the range from about 1:01 to about A and in the preferred embodiment of this invention in which a protective amount of desloratadine YO of a pharmaceutically acceptable antioxidant and no water-insoluble basic calcium salt are present in the direct release bed containing desloratadine and in its place is present on 0

1 z at least one of the preferred two acceptable antioxidants, Jie Liana Sodium edetate and citric acid and the amount of microcrystalline cellulose is increased and in addition. When a pharmaceutically acceptable antioxidant is used instead of a basic, water-insoluble calcium, magnesium, or aluminum salt, the povidone in the extended-release layer is substituted © with another binder, preferably low viscosity hydroxypropyl methylcellulose (‘MPMC’) 2910 ‎ HPMC

| The oral dosage formulation in this invention gives a shelf life of up to VA one month as long as the tablets are stored in standard containers between "m" and "Fr" in ambient ll at 60 percent relative humidity.

Vs When preparing the two-layer disc, the direct release layer was compressed first, then the second direct release layer was added on top, and sufficient compressive force was exerted to form the s-stack lS layers in the range of 8-17 kN, preferably about 9 kN. (KN) The dried extended-release granules were then ground and mixed with the required amounts of silicon dioxide and magnesium stearate and in a preferred embodiment; A pharmaceutically acceptable Vo blue dye containing EDTA was used as a chelating agent in the desloratadine direct release layer. It is preferable to use a pharmaceutical grade blue dye such as FD&C blue for aluminum lacquer (VY 07 Example 1 illustrates this JU Preparation of the preferred oral dosage formulation in this invention and the ingredients and specific quantities thereof are mentioned below: A) Direct release layer manufacturing method 1) Prepare a paste by distributing the kneaded portion of cornstarch in pure water in a suitable container equipped with a device shake. ”) and during Jalil) heat the contents until about; 2090 Bila on temperature © for about ye minutes.

Vom After step 7 is completed add an additional amount of pure water and allow the starch paste to cool (200 yen) until about Add desloratadine to the starch paste and continue mixing during step (Jalal) and during granulation 8 as an agent. EDFA No. ¥ Content FD&C Run blue aluminum lacquer (0© chelate) as Spectra blue medium dye to spray with required amount of calcium phosphate colin dibasic through sieve or pulverizer Apply dicalcium phosphate dihydrate The remaining base, the ground material from Step 1 (©), 1 part corn starch and 1 part fine crystalline cellulose into an appropriate moving bed curing bowl and then place the curing bowl into the moving bed processor. Until the temperature of the product reaches (VY), start granulating the powder by pumping the starch paste from step; into (A).

VY the moving bed with a suitable spray rate and bed temperature at approx. Continue to dry the granules at an inlet air temperature of about 10*C until 4) has been completed by ? % or less. (LOD) A final loss after drying is reached No Pass the dried granules through a suitable sieve or pulverizer. Fine crystalline cellulose, cornstarch and talc and mix for 0 minutes. B) Make extended release mixture and alcohol into a suitable container fitted with a stirrer. A Put water 1) 10 minutes Dissolve povidone in water mixture / alcohol and continue mixing for at least “. Mix the hydroxypropyl methylcellulose, psoraephedrine sulfate (*) and microcrystalline cellulose in a suitable shaker. Granulate the mixture with the povidone solution using an additional water/alcohol mixture. Yo if it is necessary to obtain the appropriate particle texture

-11-

©) Dry the wet granules at about 0"m in a suitable desiccator until the loss after drying (LOD) is between 1% and ©%.

3) Pass the dried granules through a suitable sieve or grinder.

(V) Put the ground granules into a suitable mixing device.

(A) Pass the silicon dioxide through a © grid into the mixer.

4) Mix the required amount of Magrilled Silicon Dioxide with the granules for about 10 minutes in a suitable mixer.

01. Pass the magnesium stearate through screen mesh No. (0).

1) Mix the required amount of magnesium stearate with the mixture obtained from

0 Step 4 for © minutes.

c) pressing:

Press the mixtures up to the boundaries of the bilayer tablets using a suitable bilayer tablet press using a compressive force of 4 kN and compress the extended release layer first. Bll mg + © v5900 Disc: jee Vo

-Extended Release Layer: You mg + © percent

Direct release film: 001 mg + * per cent Hardness: SCU lb + 01 (strong cup unit). The next bilayer disc was prepared using the previous method.

17 ºC: Desloratadine direct release layer, asa | Ph.Eur [USP]/ 11.2007 (European Pharmacopoeia) Microcrystalline Cellulose JP /PhEur [NF (Japanese Pharmacopoeia Fry) That AFR Ph.Eur [USP] Lacquer Aluminum Blue FD&C No. 7 5579 YA Purified Water a Ph.Eur [USP Total You and Pseudoephedrine Sulfate Extended Release Layer Pseudoephedrine Sulfate USP M-Hydroxypropyl Methylcellulose 018 Ph.Eur/ USP Microcrystalline Cellulose 7708 0000010 Centipoise Yoo, JP/Ph.Eur/nf Povidone YA,” JP/Ph.Eur/ USP Silicon Dioxide os NF Magnesium Citrate JP/Ph.Eur/NF (Non-Bovine) P. Water Pure Ph.Eur [USP | SS Alcohol 3A [USP] Alcohol — total Yo, total tablet go,

cm -1 Hardness SCU 560 +71 (strong cup unit) Example? The method described in example 1 was used; disodium edetate was used in place of the dibasic calcium salt and the amount of microcrystalline cellulose was increased in the DL 0 layer and disodium edetate was used in the extended release layer and hydroxypropyl methylcellulose 7901 was used instead of povidone. Desloratadine Direct Release Layer Desloratadine » Flour 0 Corn Starch, Ph Eur /NF, Microcrystalline Cellulose, JP/Ph.Eur/NF, Mal Disodium Edetate,| 8,4 That's AFR Ph.Eur/USP Blue 7719© Aluminum Lacquer FD&C No. No Y Purified Water Ph.Eur/USP =— Agma Yoo, Desleodeoephedrine Sulfate Extended Release Layer Pseudoephedrine Sulfate USP mL Hydroxypropyl Methylcellulose 77006 016 Ph.Eur/USP : Microcrystalline Cellulose 0 JP/Ph.Eur/NF SG Sodium edetate v.0 Hydroxypropyl Methylcellulose + 'v0' JP/Ph.Eur/USPY4) silicon dioxide NF 0, magnesium stearate JP/PhEur/NF (non-bovine) m sla pH.Eur/USP — alcohol 3A/USP alcohol SS Total Total Disk ,£0

-19- (strong cup unit). SUC 4 + 01 Hardness: 0 Example 1 mg of acid The method described in the example was used but 1 mg was added and the amount was reduced Microcrystalline Cellulose DL Citric to Layer Desloratadine Direct Release 0 ass

Y.0 Desloratadine Flour Ph.Eur /NF Corn Starch Disodium Edetate 8.4 Vo Citric Acid Crystalline Cellulose Flour JP/Ph.Eur/NF m l

AFR Ph .Eur/USP Talc Blue 7797© Aluminum Lacquer FD&C No. Y 10 _— Ph Eur/USP Purified Water Total M Dislo[Ephedrine Sulfate Release Film Extended Tee Te Pseudoephedrine Sulfate YY , USP Hydroxypropyl Methylcellulose 17T 016 011

Ph.Eur/USP Centipoise Microcrystalline Cellulose JP/Ph.Eur/NF M Disodium EDATE M Hydroxypropyl Methyl Cellulose 01 7901 Silicon Dioxide NF 8,4 Magnesium Stearate JP/PhEUr/NF (Non-Bovine) X.0 Purified Water Ph Eur/USP b Alcohol 3A/USP Alcohol — Total to 0 Tablet Total, £04

hardness: 010 + ; SUC (unit cup) (sf; example; the method described in Example 1 was used where the layered SE disc was modified in 1 JE by applying ∼mg of desloratadine in the GY layer) © Direct (YE hour dose) with appropriate changes in amounts of other ingredients and use of pseudoephedrine extended-release film for the 11 hour dose in Example 1. Hardness: 01 + sUC (strong cup unit). Desloratadine Direct Release Layer of ESE Desloratadine Micro8 Lis Atom Ph.Eur /NF Rla SB Dibasic Calcium Phosphate Hydrate oY,” 0 Microcrystalline Cellulose YV,VY JP /Ph.Eur/NF Talc Yo Ph.Eur/USP Blue 7677© aluminum lacquer FD&C No. YA Y Pure Water Ph Eur/USP SS Total 01 and 01 primer Desleodeoephedrine Sulfate Extended L-0003|EET Pseudoephedrine Sulfate USP 6-Hydroxypropyl fe-cellulose .7T Yeo, 01cP Ph.Eur/USP Microcrystalline Cellulose JP/Ph Bur/NF m Povidone YA,” JP/Ph.Eur/USP ,

—¥y—

Oy NF Silicon Dioxide Magnesium Stearate 10/01.207/117 (Non-Bovine) & E|SS Ph.Eur/USP Purified Water = Alcohol BA/USP Alcohol Total M £ 0, total disk Example e layer in AE and disk 1 modified The method described in the example was used; By replacing the dibasic calcium phosphate dihydrate in the JE layer with 1 mg of disodium edetate and increasing the amount of crystalline cellulose 01 direct release with (strong cup units). SCU 4 + 01 mg Hardness: Y,V Precision by Desloratadine Direct Release © layer

VV

84 Desloratadine, accurate

AYE Ph.Eur /NF Corn starch

YEY,V JP/Ph.Eur/NF Microcrystalline Cellulose Disodium Editate CP 1. Ph.Eur/USP That's VY Y No. FD&C Blue Aluminum Lacquer — Ph Eur/USP pure water

Yous Total F Pseudoephedrine Sulfate Extended Release Class M USP Pseudoephedrine Sulfate 0168 0110001 716 Sellen Hydroxypropylmethyl

Ph Eur/USP Centipeoise

Microcrystalline L-cellulose 1. JP/Ph.Eur/NF Hydroxypropyl methylcellulose Ve, 1901 Disodium edetate m Silicon dioxide oO, NF Magnesium stearate JP/PhEur/NF (non-bovine) Grass Purified water a Ph.

Eur/USP alcohol 3A/USP alcohol SS total vous total weight of the disc ,00 Example + The bilayer disc in the © example has been modified by adding ? mg of citric acid to the direct release layer and reduce the amount of crystalline cellulose Gal by 7.7 mg and use the extended release layer of pseudoephedrine in Example 1. Hardness: SCULLY. © (strong cup units). Desloratadine Direct Release Layer for EET, Desloratadine » Flour, 8 Wa Corn Ph.Eur /NF, Microcrystalline Cellulose, VEY JP/Ph.Eur/NF, Disodium Edetate, Yo, Citric Acid Yo That's Ph.Eur/USP 1. Blue Aluminum Lacquer Dye FD&C Blue No. NUR Y Pure Water Ph.Eur/USP Just Total Yoo and

Pseudoephedrine Sulfate Extended Release Layer ET Pseudoephedrine Sulfate YY, USP Hydroxypropyl Methylcellulose AT 016 001 : Centipoise Ph.Eur/USP Microcrystalline Cellulose JP/Ph.Eur/NF LS-Hydroxy Propyl Methyl Cellulose 0 7901 Disodium Edetate M Silicon Dioxide NF © Magnesium Stearate JP/Ph.Eur/NF (Non-Bovine) M Purified Water Ph.Eur/USP SS Alcohol 3A/USP Total alcohol cm The total weight of the tablet is 984 The dissolution pattern was measured in the laboratory for the tablets mentioned in Examples 1 to +1 in a 1.1 N solution of 1101 stirred at 2°YY (the first hour) and thereafter in Stirred phosphate buffer solution having a pH of V.0 at 717”C then 80 in All of 0 desloratadine was dissolved in the direct release layers during the first 30 minutes and the total dose of pseudoephedrine sulfate was released in the extended release layers slowly through fragmentation and dissolution mechanisms for at least VY hours (with NY being 45% in 1 hour, +10.5-50% in 2 hours, >80% in >7 hours) and results are expected. Similar if an effective decongestant amount is used N0 - Another pharmaceutically acceptable pseudoephedrine salt such as pseudoephedrine hydrogen chloride instead of pseudoephedrine sulfate. The compositions of this invention are useful in the treatment of allergic conditions and/or infections affecting the skin (such as urticaria) and the lower and upper airways, including

Both nasal and non-nasal symptoms of seasonal allergic rhinitis (Lay) have Cod congestion in patients who need this treatment, and the specific dose and dosing regimen can be different according to the attending physician in the light of what has been mentioned here depending on the patient’s requirements such as the patient’s age, type, and unit. Allergy and/or inflammation to be treated is 0 and determining the appropriate dosage and dosing regimen for a particular patient is within the scope of the attending physician's expertise. Whilst a number of preferred embodiments of this invention have been mentioned previously in the 0 way JER it is clear that the scope of this invention is limited by the scope of the appended claims.

Claims (1)

Protective Elements 1-1 A solid, compressed, two-layer formula consisting of (1) a first layer containing an effective anti-allergic amount of desloratadine and a protective amount and desloratadine of a calcium, magnesium or aluminum base salt that is insoluble 3 in water is acceptable Pharmaceutical or from a protective amount of desloratadine from at least one pharmaceutically acceptable antioxidant ° (V5) a second layer containing 1 effective quantity of pseudoephedrine or its Jog salt as a pharmaceutically acceptable excipient and optionally on 7 of one quantity of desloratadine from a pharmaceutically acceptable antioxidant. 1 "- A solid, bilayer compressed formulation consisting of 1) a first layer containing an effective antiallergic amount of desloratadine and a protective amount of desloratadine from at least one pharmaceutically acceptable antioxidant and 7) a second layer ¢ containing an effective amount of pseudoephedrine or Salt and on a pharmaceutically acceptable excipient, and on a pharmaceutically acceptable amount of anti-oxidant protection for desloratadine. A basic calcium, magnesium or aluminum salt, insoluble in water, pharmaceutically acceptable 5 (Y). A second layer containing an effective amount of pseudoephedrine or its salt. 1- A solid, bilayer compressed formulation consisting of a) a first/direct release layer containing an effective antiallergic amount of desloratadine and at least one pharmaceutically acceptable ¥ excipient and b) a second extended release layer containing ¢ an effective amount of a decongestant The nose and on a pharmaceutically acceptable excipient where they are Y a — _ 9 The total amount of desloratadine degradation products is less than about ? percent. —o 1 The solid, compressed, bilayer composition described in any of the preceding items wherein the first layer is a direct release layer Gay ¥ the second layer is an extended release layer containing a pharmaceutically acceptable extended release agent 3 . 1 - The solid, bilayer compressed formulation described in element © where Y is the nasal decongestant pseudoephedrine or its pharmaceutically acceptable salt. 1 7"- bilayer compressed solid composition described in any of the preceding Item Y in which at least 40 percent of desloratadine dissolves in a solution of 0.11 7 N HCI at 2°YY at approximately £ 0 min.1 8- The solid, compressed, bilayer formulation described in any of the preceding 1 items wherein the amount of A1-formyldesloratadine is less than about #85 in and percent after storage at “C and 1 percent nM for an extended period of time 3. 14- The described bilayer compressed solid is in either element 1 Y or Y wherein about 1 in Lal to about a percent of a pharmaceutically acceptable antioxidant Al is present in each layer. -0 1 The solid, bilayer compressed formulation described in any of the ¥ preceding items in which the antiallergic effective quantity of desloratadine in the first layer is approximately 0.¥ mg. The L-1-1 is the bilayer compressed solid composition described in any of the foregoing Y items in which the effective antiallergic amount of 3-desloratadine in the first layer is approximately © mg. 1 | - The solid, compressed, bilayer composition described in item 1 or X Y where two pharmaceutically acceptable antioxidants are present in the class and desloratadine. (VY 1) The two-layer compressed solid composition described in 1 or ¥ Gan Y in which the first direct release layer contains: desloratadine; Y,o flour Maize starch INF European Pharmacopoeia RI © (Constitution USP Dibasic Calcium Phosphate Hydrate JB American Valleys)/ 211.107 (European Pharmacopoeia) Microcrystalline Cellulose JP [Ph.Eur [NF] (Pharmacopoeia 1 Japanese) 8 Ph.Eur [that USP FD&C blue aluminum lacquer YA 55797 1 v 2nd extended release coat contains YY, USP Pseudoephedrine Sulfate Hydroxypropyl Methyl Cellulose Ph.Eur/ USP 6 Microcrystalline Cellulose 7758; 00001 centipoise once SerlaJP/Ph.Eur/nf YA,” JP/Ph.Eur/ USP Povidone oO, NF Silicon Dioxide Yo (Non-Bovine) JP/Ph.Eur/NF Magnesium Citrate \?- the bilayer compressed solid composition described in 1 or ? where "- In which the first direct release layer contains: Desloratadine Gaia, corn starch, microcrystalline cellulose, yo laminate, disodium edetate oO, citric acid zero - 0.1a talc, ¥ lacquer FD&C Blue Aluminum No. YA Y Total Vee v And where the second release layer contains: pseudoephedrine sulfate YY, hydroxypropyl methyl cellulose 016 YY oA fine crystalline cellulose 0 disodium edetate M-hydroxypropyl methyl cellulose 776010 l silicon dioxide oO, ‏ —_ Y 5 _ A) magnesium stearate Yo. Total 1 - Solid, compressed, bilayer formulation consisting of 1) first layer containing \i | containing Y,0 or © mg of desloratadine and a protective amount of desloratadine of the 3-calcium, magnesium, or aluminum base salt Insoluble in water and (Y ¢ second coat containing YY. mg of pseudoephedrine or its salt and over 2 pseudoephedrine is pharmaceutically acceptable. 1 - Compressed, bilayer solid formulation consisting of 1) first coat 1) contain 7.5 or © mg of at least one pharmaceutically acceptable antioxidant and Y 2 mg of pseudoephedrine or its salt and together YY a second layer containing i ¢ pharmaceutically acceptable and a protective amount of desloratadine At least one pharmaceutically acceptable anti-oxidant. YY 1 The two-layer compressed solid composition described in item 11 or . L 0 in which the amount of desloratadine in the first layer is about 1.5 mg. 18- The solid bilayer compressed formulation described in either VO or Cun 11 in which the amount of desloratadine in the first layer 7 is approximately 2 mg. 1 - The solid, compressed, two-layer composition described in item 1 or Y "in which the first direct release layer contains: and desloratadine direct release layer oo en hid a n1 component 8, 4 Desloratadine Flour 10 Ph.Eur /NF Corn Ws ov, Basic JL 5 Dicalcium Phosphate Dihydrate Ph.Eur/USP YY, VY JP/Ph.Eur/NF Fine Crystalline Cellulose Ye Ph.Eur/USP Tin “YA Y FD&C Blue No. 01YY Pigment Aluminum Lacquer — Ph Eur/ USP Purified Water 01W Total Pseudoephedrine Sulfate Extended Release Class 1 0 EUR USP Pseudoephedrine Sulfate 018 000001 714 Hydroxypropyl Methylcellulose Ph.Eur/USP centipoise Vou, JP/Ph.Eur/NF Microcrystalline cellulose YA, JP/Ph.Eur/USP Povidone 0,” NF Silicon dioxide Yo (non-bovine) ) JP/Ph.Eur/NF Magnesium Stearate _ Ph.Eur/USP Purified Water Alcohol SSPP 3A/USP Alcohol BE Total 0+,” Tablet Total or 1 The solid, compressed, two-layered composition described in element Yo 1, in which the first direct-release layer contains: Y Desloratadine direct-release layer 3 HA: Deslor! 1m Corn Starch Ph.Eur /NF 1m Microcrystalline Cellulose VEY, V=V EY JP/Ph.Eur/NF Disodium edetate 00 Ph.Eur/USP "m Aluminum lacquer Blue FD&C No. Y 1 Purified Water Ph Eur/USP _Total ED + Pseudoephedrine Sulfate Extended Release Layer Pseudoephedrine Sulfate VY, USP Hydroxypropyl die Cellulose 016 7718 00 clp Ph. Eur/USP Microcrystalline Cellulose JP/Ph.Eur/NF M Hydroxypropyl Methyl Cellulose 7901 0 JG Sodium Edetate 7, Silicon Dioxide 117 8:4 Magnesium Stearate JP/Ph.EUr/NF (Non-Bovine) m Purified Water Ph Eur/USP -_ Alcohol 3A/USP Total Alcohol You, 0 Sat Weight | In which of the above items where the total amount of desloratadine degradation products is less than mcn Js? percent. Schematic table 0 º cl 7 ". 2 7 1 5 | A ) it 1 Cl 74 \ Ci { 2 =N = OH > ca nF wi i ; 7 11 Vi { Cl : OH Vv